BRCA MUTATION STATUS AND SENSITIVITY TO CHEMOTHERAPY

Sensitivity to First-Line Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Mieke Kriege, Caroline Seynaeve, Hanne Meijers-Heijboer, J. Margriet Collee, Marian B.E. Menke-Pluymers, Carina C.M. Bartels, Madeleine M.A. Tilanus-Linthorst, Jannet Blom, Elisabeth Huijskens, Agnes Jager, Ans van den Ouweland, Bert van Geel, Maartje J. Hooning, Cecile T.M. Brekelmans, Jan G.M. Klijn

From the Family Cancer Clinic, Departments of Medical Oncology, Oncological Surgery, and Clinical Genetics Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.

Corresponding author: Mieke Kriege, PhD, Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; e-mail: a.kriege@erasmusmc.nl.

Purpose Preclinical as well as a few small retrospective, neoadjuvant studies suggest that breast cancer (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to some chemotherapeutic agents causing double-strand DNA breaks. In this study we assessed the sensitivity to standard first-line chemotherapy of metastatic BRCA1/2-associated breast cancer, compared with sporadic breast cancer patients.

Patients and Methods From the Family Cancer Clinic database, we selected 93 BRCA1- and 28 BRCA2-associated breast cancer patients treated with chemotherapy for metastatic disease before January 1, 2007. Objective response (OR), progression-free survival (PFS), and overall survival (OS) after start of first-line chemotherapy were compared with those of sporadic patients, matched for year of birth, age at diagnosis of primary breast cancer, and year of detection of metastatic disease.

Results The chemotherapy regimens most frequently used were anthracycline-based (n = 147) and cyclophosphamide, methotrexate, and fluorouracil (CMF)/CMF like (n = 68). As compared to sporadic patients, BRCA2-associated patients had a significantly higher OR (89% v 50%; P = .001), a longer PFS (hazard ratio multivariate [HR_mult] 0.64; P = .04) and a prolonged OS (HR_mult, 0.53; P = .005) after start of first-line chemotherapy for metastatic breast cancer. For BRCA1-associated patients, a nonsignificant trend for an increased OR (66% v 50%; P = .07), and a longer PFS (HR_mult, 0.79; P = .14) after first-line chemotherapy for metastatic breast cancer was observed, but not for OS.

Conclusion BRCA2-associated breast cancer is more sensitive to standard first-line chemotherapy for metastatic breast cancer in comparison with sporadic breast cancer, especially to anthracyclines. For BRCA1-associated breast cancer no statistically significant higher sensitivity was observed.